Tg737orpk mice have defects in cilia assembly and develop hydrocephalus in the perinatal period of life. Hydrocephalus is progressive and is thought to be initiated by abnormal ion and water transport across the choroid plexus epithelium. The pathology is further aggravated by the slow and disorganized beating of motile cilia on ependymal cells that contribute to decreased cerebrospinal fluid movement through the ventricles. Previously, we demonstrated that the hydrocephalus phenotype is associated with a marked increase in intracellular cAMP levels in choroid plexus epithelium, which is known to have regulatory effects on ion and fluid movement in many secretory epithelia. To evaluate whether the hydrocephalus in Tg737orpk mutants is associated with defects in ion transport, we compared the steady-state pHi and Na+-dependent transport activities of isolated choroid plexus epithelium tissue from Tg737orpk mutant and wild-type mice. The data indicate that Tg737orpk mutant choroid plexus epithelium have lower pHi and higher Na+-dependent HCO-3 transport activity compared with wild-type choroid plexus epithelium. In addition, wild-type choroid plexus epithelium could be converted to a mutant phenotype with regard to the activity of Na+-dependent HCO-3 transport by addition of dibutyryl-cAMP and mutant choroid plexus epithelium toward the wild-type phenotype by inhibiting PKA activity with H-89. Together, these data suggest that cilia have an important role in regulating normal physiology of choroid plexus epithelium and that ciliary dysfunction in Tg737orpk mutants disrupts a signaling pathway leading to elevated intracellular cAMP levels and aberrant regulation of pHi and ion transport activity. Copyright © 2007 the American Physiological Society.